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Molecular studies on ASPP and FBI-1 in gestational trophoblastic diseaseMak, Chun-yin., 麥俊然. January 2012 (has links)
Gestational trophoblastic disease (GTD) encompasses a heterogeneous group of trophoblastic lesions. It includes hydatidiform mole (HM), choriocarcinoma (CCA), placental site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT). While the latter three are classical malignancies, HM represents abnormal placenta harbouring malignant potential and may develop persistent gestational trophoblastic neoplasm (GTN) requiring therapy. Apoptotic activity and p53 are known to be important in pathogenesis of GTD. However, understanding on the underlying mechanisms is still limited.
ASPP1 and ASPP2 are the two tumour suppressor members of the apoptosis stimulating protein of p53 (ASPP) family that stimulate p53-dependent apoptotic pathway. In this study, a differential downregulation of ASPP1 and ASPP2 was observed in GTD, illustrating their distinct roles in the pathogenesis. Results showed that both ASPP1 mRNA and protein levels were significantly downregulated in HM and CCA, when compared with normal placentas by quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Methylation-specific polymerase chain reaction (MS-PCR) in placenta and GTD samples demonstrated a significant correlation between ASPP1 mRNA level and their hypermethylation status (P = 0.024). Most importantly, lower ASPP1 immunoreactivity was found in HM that progressed into persistent GTN than HM that regressed (P = 0.045). Significant correlation was also found between expression of ASPP1 and apoptotic activity (M30 CytoDeath index), p53 and caspase-8 immunoreactivities. In CCA cell lines, namely JEG-3 and JAR, ectopic expression of ASPP1 triggered apoptosis through intrinsic and extrinsic pathways as indicated by an increase in cleaved caspase-9 and Fas ligand protein expression, demonstrating a potent tumour suppressive function through its proapoptotic nature.
Downregulation of ASPP2 was mainly detected in choriocarcinoma, the most aggressive form of GTD. In vitro, results showed that ASPP2 was a multi-functional protein with activities not limited to apoptosis stimulation. While activated Src is important in tumour progression, transfection of ASPP2 but not ASPP1 was found to be related to decreased Src-pY416 phosphorylation. This suggested an inactivating effect of ASPP2 on Src. Moreover, this ASPP2-induced inactivation of Src could be abolished by RNA interference (RNAi) with Csk small interfering RNA. Corresponding effect on aggressive behaviors such as cell migration was also confirmed. Hence, loss of ASPP2 in the choriocarcinoma implicates its crucial role in tumourigenesis.
FBI-1 is a transcription factor frequently overexpressed in human cancers. Recently, overexpression of FBI-1 in GTD in association with GTN development was also reported. However, its role in GTD pathogenesis remains elucidated at molecular basis. This study unveiled the ability of FBI-1 in contributing overt aggressiveness in GTD. Ectopic FBI-1 expression resulted in decrease in apoptosis and repression of pro-apoptotic genes such as Bak, Fas and caspase-8 at mRNA level in vitro. FBI-1 overexpression also promoted Akt activation as indicated by Akt-pS473 phosphorylation. Interestingly, effect of FBI-1 on cell motility and invasiveness was eradicated in the presence of specific PI3 kinase inhibitor LY294002. This demonstrated that FBI-1 could promote cell migration and invasion through PI3K/Akt signaling.
In summary, this study highlighted the effects of dysregulated ASPP and FBI-1 in apoptosis and aggressiveness, implicating their crucial roles in pathogenesis in GTD. / published_or_final_version / Pathology / Doctoral / Doctor of Philosophy
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FBI-1 and choriocarcinoma cell proliferationCheung, Man-keung, 張文強 January 2013 (has links)
Gestational trophoblastic disease (GTD) includes a spectrum of diseases that involve abnormal growth of trophoblastic cells inside the uterus. It can range from benign hydatidiform moles (HM) to frankly malignant choriocarcinoma, placental site trophoblastic tumor (PSTT) or epithelioid trophoblastic tumour (ETT).GTD are considered curable if the patient is correctly diagnosed and receive appropriate treatment during the early stage of the disease.
About 15% -30% of hydatidiform moles will develop persistent GTD, but majority of them can usually resolved by surgical intervention and post-operation weekly serial serum β-hCG level monitoring. In contrast, choriocarcinoma is a frankly malignant gestational trophoblastic neoplasm (GTN). Most choriocarcinoma arise from HM but can develop from any pregnancy related events such as ectopic pregnancy, live-birth or stillbirth. Being the most aggressive neoplasm in GTD, choriocarcinoma can develop widespread metastasis and can be fatal.
FBI-1 (Pokemon) is a transcription factor that is often overexpressed in various types of human cancer. We have reported overexpression of FBI-1 in ovarian cancer in association with cell proliferation and invasiveness. Our recent study also suggested that overexpression of FBI-1 in HM was related to subsequent development of gestational trophoblastic neoplasms(GTN).
In this study, we evaluated the role of FBI-1 inchoriocarcinoma cell proliferation. By MTT assay, the proliferation rates of two choriocarcinoma cell lines (JAR and JEG-3) was found to decrease when FBI-1 was downregulated by shRNA approach with statistical significance reached in JEG-3 (p < 0.05). By quantitative real time PCR, the relative levels of a panel of hedgehog pathway related genes, including SHH, SMO, GLI1, GLI2, GLI3, and KIF7 were assessed after knockdown of FBI-1 gene. Sonic hedgehog (SHH) was found to be consistently downregulated in JEG-3 and JAR transfected with FBI-1 shRNA constructs.
In conclusion, FBI-1 may play a role in choriocarcinoma cell proliferation and FBI-1 may be explored as a potential therapeutic target for GTD in the future. / published_or_final_version / Pathology / Master / Master of Medical Sciences
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The effects of 5-aza-2'-deoxycytidine and trichostatin A on FBI-1 gene expression in choriocarcinoma cell linesChan, Sze-wai, Cicilia, 陳思慧 January 2014 (has links)
Choriocarcinoma is a rare, aggressive malignant epithelial tumor that can be arisen from gestational or non-gestational origins. Gestational choriocarcinoma is found primarily in uterus and is a malignant form of gestational trophoblastic disease. The tumor can easily metastasize to other organs through blood vessels and fatal outcome would be resulted if untreated. Nevertheless, the underlying pathogenesis is not fully explored and understood.
FBI-1 is a proto-oncogene and acts as a transcriptional repressor for many cellular processes. Overexpression of FBI-1 was observed in various types of cancers including gestational choriocarcinoma. However, little is known on the mechanisms of regulation of FBI-1 gene expression. In this study, by treating with two epigenetic remodeling drugs, 5-aza-2’-deoxycytidine (5-aza-dc) and trichostatin A (TSA), mRNA and protein expressions of FBI-1 were investigated in gestational choriocarcinoma cell lines, JEG-3 and JAR by using quantitative real-time PCR and western blotting. The morphological changes and cell survival after treatment of 5-aza-dc or TSA on JEG-3 and JAR cell lines was also assessed, the latterby3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) assay.
This study demonstrated that FBI-1 protein was overexpressed in JEG-3 and JAR cells compared to normal trophoblastic cell line. Moreover, FBI-1 expressions in JEG-3 and JAR cells were down-regulated in TSA treatment but remained unchanged in 5-aza-dc treatment. It implies that HDAC inhibitor is able to regulate the expression of FBI-1 gene.
After treatment with TSA at 0.3Mor 0.6M, both JEG-3 and JAR cells demonstrated significant morphological changes when comparing with the untreated controls, becoming elongated, distorted, rounder and smalleras well as increasingly detached and floating suggestive of cell death. Such changes were not significantly observed in 5-aza-dctreated cells. In addition, more significant reduction in cell survival as assessed by MTT assay was found in TSA than in 5-aza-dc treatment. This may be related to the decrease inFBI-1 expression after TSA treatment.
In summary, histone modification may play a role in the regulation of FBI-1 expression in gestational choriocarcinoma cells affecting the cell survival. / published_or_final_version / Pathology / Master / Master of Medical Sciences
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Immunological studies in gestational trophoblastic disease /Ho, Pak-chung. January 1900 (has links)
Thesis (M.D.)--University of Hong Kong, 1990.
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Immunological studies in gestational trophoblastic diseaseHo, Pak-chung. January 1900 (has links)
Thesis (M.D.)--University of Hong Kong, 1990. / Also available in print.
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Pathobiological study of gestational trophoblastic diseaseCheung, Nga-yin, Annie. January 1999 (has links)
Thesis (M.D.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 157-201) Also available in print.
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Pokemon and pak interactive exchange factor alpha in gestational trophoblastic diseases吳惠茵, Ng, Wai-yan. January 2008 (has links)
published_or_final_version / Medical Sciences / Master / Master of Medical Sciences
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The ASPP family in gestational trophoblastic diseaseLee, Lee, 李莉 January 2008 (has links)
published_or_final_version / Medical Sciences / Master / Master of Medical Sciences
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PAK1, PAK2 and PAK4 in gestational trophoblastic disease楊雋永, Yeung, Chun-wing. January 2008 (has links)
published_or_final_version / Pathology / Master / Master of Research in Medicine
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Genotyping of gestational trophoblastic diseaseLai, Yau-lin, Caroline. January 2001 (has links)
Thesis (M. Med. Sc.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 49-58).
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